This Phase II SBIR program aims to develop and demonstrate an innovative AC measurement system for measuring ionic current in biological and artificial nanoscale channels. Nanopores and nanochannels represent a key emerging component of nanotechnology, as well as a continuing focus of much biophysical and pharmacological research. AC measurement enables new time and amplitude degrees of freedom, such as measurement of the unbiased (zero DC) properties of analyte binding interactions, and new opportunities to study fundamental phenomena. A particular benefit of AC probing is that it permits a significant improvement in measurement sensitivity. In Phase II, our goal is to demonstrate the full capability of the AC method through construction of an optimized sensing platform. Many aspects of this platform will be taken from an ongoing DARPA funded effort to develop protein pore measurement technology for use outside the laboratory, and this Phase II effort will make a number of significant practical advances available to the research community. Specific Phase II objectives are to build a prototype AC system that provides a net increase in measurement signal-to-noise ratio of 10 over present commercial technology, and to demonstrate its capability in an area of active research. The Phase II system will be offered to the research community as an integrated standalone system for basic measurements under the product name: Individual Molecule Analysis Platform (IMAP). A particular application of the AC method is that it potentially offers a means to sequence DNA at a cost much lower than any method that relies on chemical reagents. The potential performance was studied in Phase I with excellent results, and we will continue this effort in Phase II. Indeed, preliminary calculations that were updated based on the Phase I results show that it is just possible that the Phase II system will be able to differentiate the bases of DNA in a true sequencing modality. However, even if that tremendous result is not achieved, the Phase II prototype will provide the next generation in nanopore ionic current measurement capability. PUBLIC HEALTH RELEVANCE: Nanoscale biological channels underlie many of the basic physiologic properties in the body and are targeted by approximately 13% of all pharmaceuticals. In addition, artificial nanoscale structures offer tremendous possibilities to improve medicine and advance basic scientific understanding of molecular processes. The workhorse technology to study such channels and structures has not advanced in 10 years. This program will provide experimental results that were not previously possible, and greatly improve the methods ease of use, thereby reducing operational costs and making the capabilities more available to new researchers.